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Single-nucleotide polymorphisms in the ?-adrenergic receptor genes are associated with lung allograft utilization.

ABSTRACT: Pulmonary edema and associated impaired oxygenation are a major reason for rejection of donor lung allografts offered for transplantation. Clearance of pulmonary edema can be upregulated by stimulation of ?-adrenergic receptors (?ARs). Single-nucleotide polymorphisms (SNPs) in ?AR genes have functional effects in vitro and in vivo. We hypothesized that SNPs in ?AR genes would be associated with rates of utilization of donor lung allografts offered for transplantation.Nine hundred fifty-one organ donors were genotyped for 4 amino-acid-coding SNPs in the ?AR genes. Lung allograft utilization was compared among donors stratified by genotypes.Utilization of donor lung allografts was 55% vs 35% (p = 0.02) among donors with GG vs AA/AG genotypes of the Ser49Gly SNP, 39% vs 32% (p = 0.04) with GG vs AA/AG genotype of Gly16Arg SNP and 37% vs 32% (p = 0.1) with CC vs GC/GG genotype of the Arg389Gly SNP. In the combined analysis, donors carrying 0 or 1 associated genotype had a utilization rate of 33%, whereas donors carrying 2 or 3 associated genotypes had utilization rates of 44% and 58%, respectively (p = 0.008). There was a stepwise decrease in chest radiograph infiltrates and an increase in partial pressure of oxygen/fraction of inspired oxygen (PaO(2)/FIO(2)) with an increasing number of these associated genotypes.Genetic variants in the ?AR genes among organ donors are associated with higher rates of lung allograft utilization. The increased utilization may be related to increased clearance of pulmonary edema and improved oxygenation in donors with favorable genotypes and suggests that ?AR agonists may have a role in donor management.

SUBMITTER: Sapru A

PROVIDER: S-EPMC3019270 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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Single-nucleotide polymorphisms in the β-adrenergic receptor genes are associated with lung allograft utilization.

Sapru Anil A Pawlikowska Ludmila L Liu Kathleen D KD Khush Kiran K KK Ann-Baxter-Lowe Lee L Hayden Vanessa V Menza Rebecca L RL Convery Maureen M Poon Annie A Landeck Megan M Zaroff Jonathan G JG Matthay Michael A MA

The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation 20110201 2

<h4>Background</h4>Pulmonary edema and associated impaired oxygenation are a major reason for rejection of donor lung allografts offered for transplantation. Clearance of pulmonary edema can be upregulated by stimulation of β-adrenergic receptors (βARs). Single-nucleotide polymorphisms (SNPs) in βAR genes have functional effects in vitro and in vivo. We hypothesized that SNPs in βAR genes would be associated with rates of utilization of donor lung allografts offered for transplantation.<h4>Metho ...[more]

PMID: 20869266

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Project description:BACKGROUND Interstitial fibrosis and tubular atrophy (IF/TA) have been recognized as crucial factors contributing to graft loss resulting from chronic renal allograft injuries. Recent studies have indicated a significant association between the progression of organ fibrosis and single nucleotide polymorphisms (SNPs) found on certain genes. Our research sought to understand these potential associations and detect the potential impact of SNPs on ubiquitin-related genes related to allograft fibrosis in kidney transplant recipients. MATERIAL AND METHODS There were 200 patients enrolled in this study, from which samples were extracted for total DNA. Targeted next-generation sequencing was used to detect SNPs on 9 genes (FBXL21, PIAS1/2, SUMO1/2/3/4, UBE2D1, and UBE2I). Minor allele frequency (MAF) and Hardy-Weinberg equilibrium (HWE) tests were used and followed by linkage disequilibrium analysis. General linear models (GLM) were used to identify significant confounding factors. Finally, multiple inheritance models and haplotype analyses were conducted to explore associations between SNPs and the degree of the severity of renal allograft fibrosis. RESULTS In total, 144 SNPs were identified in targeted sequencing. After filtering based on results from MAF and HWE tests, 15 tagger SNPs were selected for further analyses of associations. GLMs indicated that the administration of sirolimus significantly contributed to the degree of severity of allograft fibrosis (P=0.011). After adjusting for confounding factors and applying a Bonferroni correction, multiple inheritance model analyses indicated that the recessive model of rs644731 of the PIAS2 gene was significantly correlated with the occurrence of IF/TA (P=0.01). Furthermore, single-locus based analysis of rs644731 did not indicate that it had a positive influence on IF/TA in a degree-dependent manner. Finally, linkage disequilibrium analysis revealed 3 haplotypes all lacking significant correlation with respect to the IF/TA experimental cohort. CONCLUSIONS We are the first to reveal that mutations of rs644731 in the PIAS2 gene were significantly correlated with the progression of IF/TA in kidney transplant recipients.

Project description:The advent of high throughput sequencing technology has enabled the 1000 Genomes Project Pilot 3 to generate complete sequence data for more than 906 genes and 8,140 exons representing 697 subjects. The 1000 Genomes database provides a critical opportunity for further interpreting disease associations with single nucleotide polymorphisms (SNPs) discovered from genetic association studies. Currently, direct sequencing of candidate genes or regions on a large number of subjects remains both cost- and time-prohibitive.To accelerate the translation from discovery to functional studies, we propose an in silico gene sequencing method (ISS), which predicts phased sequences of intragenic regions, using SNPs. The key underlying idea of our method is to infer diploid sequences (a pair of phased sequences/alleles) at every functional locus utilizing the deep sequencing data from the 1000 Genomes Project and SNP data from the HapMap Project, and to build prediction models using flanking SNPs. Using this method, we have developed a database of prediction models for 611 known genes. Sequence prediction accuracy for these genes is 96.26% on average (ranges 79%-100%). This database of prediction models can be enhanced and scaled up to include new genes as the 1000 Genomes Project sequences additional genes on additional individuals. Applying our predictive model for the KCNJ11 gene to the Wellcome Trust Case Control Consortium (WTCCC) Type 2 diabetes cohort, we demonstrate how the prediction of phased sequences inferred from GWAS SNP genotype data can be used to facilitate interpretation and identify a probable functional mechanism such as protein changes.Prior to the general availability of routine sequencing of all subjects, the ISS method proposed here provides a time- and cost-effective approach to broadening the characterization of disease associated SNPs and regions, and facilitating the prioritization of candidate genes for more detailed functional and mechanistic studies.

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Single-nucleotide polymorphisms in the ?-adrenergic receptor genes are associated with lung allograft utilization.

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Single-nucleotide polymorphisms in the β-adrenergic receptor genes are associated with lung allograft utilization.

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